tbuckley/cabot-search huggingface dataset:
Targeting histone deacetylase suppresses tumor growth through eliciting METTL14‐modified m<sup>6</sup>A RNA methylation in ocular melanoma
Authors: Ai Zhuang, Xiang Gu, Tongxin Ge, Shaoyun Wang, Shengfang Ge, Peiwei Chai, Renbing Jia, Xianqun Fan
Journal: Cancer Communications (2023)

Abstract Background Diversified histone deacetylation inhibitors (HDACis) have demonstrated encouraging outcomes in multiple malignancies. N6‐methyladenine (m 6 A) is the most prevalent messenger RNA modification that plays an essential role in the regulation of tumorigenesis. Howbeit, an in‐depth understanding of the crosstalk between histone acetylation and m 6 A RNA modifications remains enigmatic. This study aimed to explore the role of histone acetylation and m 6 A modifications in the regulation of tumorigenesis of ocular melanoma. Methods Histone modification inhibitor screening was used to explore the effects of HDACis on ocular melanoma cells. Dot blot assay was used to detect the global m 6 A RNA modification level. Multi‐omics assays, including RNA‐sequencing, cleavage under targets and tagmentation, single‐cell sequencing, methylated RNA immunoprecipitation‐sequencing (meRIP‐seq), and m 6 A individual nucleotide resolution cross‐linking and immunoprecipitation‐sequencing (miCLIP‐seq), were performed to reveal the mechanisms of HDACis on methyltransferase‐like 14 ( METTL14 ) and FAT tumor suppressor homolog 4 ( FAT4 ) in ocular melanoma. Quantitative real‐time polymerase chain reaction (qPCR), western blotting, and immunofluorescent staining were applied to detect the expression of METTL14 and FAT4 in ocular melanoma cells and tissues. Cell models and orthotopic xenograft models were established to determine the roles of METTL14 and FAT4 in the growth of ocular melanoma. RNA‐binding protein immunoprecipitation‐qPCR, meRIP‐seq, miCLIP‐seq, and RNA stability assay were adopted to investigate the mechanism by which m 6 A levels of FAT4 were affected. Results First, we found that ocular melanoma cells presented vulnerability towards HDACis. HDACis triggered the elevation of m 6 A RNA modification in ocular melanoma. Further studies revealed that METTL14 served as a downstream candidate for HDACis. METTL14 was silenced by the hypo‐histone acetylation status, whereas HDACi restored the normal histone acetylation level of METTL14 , thereby inducing its expression. Subsequently, METTL14 served as a tumor suppressor by promoting the expression of FAT4 , a tumor suppressor, in a m 6 A‐YTH N6‐methyladenosine RNA‐binding protein 1‐dependent manner. Taken together, we found that HDACi restored the histone acetylation level of METTL14 and subsequently elicited METTL14‐mediated m 6 A modification in tumorigenesis. Conclusions These results demonstrate that HDACis exert anti‐cancer effects by orchestrating m 6 A modification, which unveiling a “histone‐RNA crosstalk” of the HDAC/ METTL14 / FAT4 epigenetic cascade in ocular melanoma.
Single Cell Multiomics Identifies Cells and Genetic Networks Underlying Alveolar Capillary Dysplasia
Authors: Minzhe Guo, Kathryn A. Wikenheiser-Brokamp, Joseph A. Kitzmiller, Cheng Jiang, Guolun Wang, Allen Wang, Sebastian Preissl, Xiaomeng Hou, Justin Buchanan, Justyna A. Karolak, Yifei Miao, David B. Frank, William J. Zacharias, Xin Sun, Yan Xu, Mingxia Gu, Pawel Stankiewicz, Vladimir V. Kalinichenko, Jennifer A. Wambach, Jeffrey A. Whitsett
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal developmental disorder of lung morphogenesis caused by insufficiency of FOXF1 (forkhead box F1) transcription factor function. The cellular and transcriptional mechanisms by which FOXF1 deficiency disrupts human lung formation are unknown.
High-Altitude Andean H194R <i>HIF2A</i> Allele Is a Hypomorphic Allele
Authors: Kelsey Jorgensen, Daisheng Song, Julien Weinstein, Obed A Garcia, Laurel N Pearson, María Inclán, Maria Rivera-Chira, Fabiola León-Velarde, Melisa Kiyamu, Tom D Brutsaert, Abigail W Bigham, Frank S Lee
Journal: Molecular Biology and Evolution (2023)

For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the hypoxia-inducible factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A and a unique pattern of variation surrounding the Andean-specific single nucleotide variant (SNV), rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m), reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, aryl hydrocarbon receptor nuclear translocator. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele.
Extending Nontargeted Discovery of Environmental Chemical Exposures during Pregnancy and Their Association with Pregnancy Complications—A Cross-Sectional Study
Authors: Jessica Trowbridge, Dimitri Abrahamsson, Garret D. Bland, Ting Jiang, Miaomiao Wang, June-Soo Park, Rachel Morello-Frosch, Marina Sirota, Harim Lee, Dana E. Goin, Marya G. Zlatnik, Tracey J. Woodruff
Journal: Environmental Health Perspectives (2023)

Background: Nontargeted analysis (NTA) methods identify novel exposures; however, few chemicals have been quantified and interrogated with pregnancy complications. Objectives: We characterized levels of nine exogenous and endogenous chemicals in maternal and cord blood identified, selected, and confirmed in prior NTA steps, including linear and branched isomers perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), monoethylhexyl phthalate, 4-nitrophenol, tetraethylene glycol, tridecanedioic acid, octadecanedioic acid, and deoxycholic acid. We evaluated relationships between maternal and cord levels and between gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy in a diverse pregnancy cohort in San Francisco. Methods: We collected matched maternal and cord serum samples at delivery from 302 pregnant study participants from the Chemicals in Our Bodies cohort in San Francisco. Chemicals were identified via NTA and quantified using targeted approaches. We calculated distributions and Spearman correlation coefficients testing the relationship of chemicals within and between the maternal and cord blood matrices. We used adjusted logistic regression to calculate the odds of GDM and hypertensive disorders of pregnancy associated with an interquartile range increase in maternal chemical exposures. Results: We detected linear PFOS, PFHxS, octadecanedioic acid, and deoxycholic acid in at least 97% of maternal samples. Correlations ranged between −0.1 and 0.9. We observed strong correlations between cord and maternal levels of PFHxS, linear PFOS, and branched PFOS (coefficient=0.9, 0.8, and 0.8, respectively). An interquartile range increase in linear and branched PFOS, tridecanedioic acid, octadecanedioic acid, and deoxycholic acid was associated with increased odds ratio (OR) of GDM [OR=1.33 (95% CI: 0.89, 2.01), 1.24 (95% CI: 0.86, 1.80), 1.26 (95% CI: 0.93, 1.73), 1.24 (95% CI: 0.86, 1.80), and 1.23 (95% CI: 0.87, 1.75), respectively]. Tridecanedioic acid was positively associated with hypertensive disorders of pregnancy [OR=1.28 (95% CI: 0.90, 1.86)]. Discussion: We identified both exogenous and endogenous chemicals seldom quantified in pregnant study participants that were also related to pregnancy complications and demonstrated the utility of NTA to identify chemical exposures of concern. https://doi.org/10.1289/EHP11546
Rates of Second Tumor, Metastasis, and Death From Cutaneous Squamous Cell Carcinoma in Patients With and Without Transplant-Associated Immunosuppression
Authors: Petter Gjersvik, Ragnhild S. Falk, Ingrid Roscher, Syed Mohammad Husain Rizvi, Geir Mjøen, Einar Gude, Inga Leuckfeld, Kirsten Muri Boberg, Marit B. Veierød, Trude Eid Robsahm
Journal: JAMA Dermatology (2023)

Cutaneous squamous cell carcinoma (cSCC) may occur with multiple primary tumors, metastasize, and cause death both in immunocompetent and immunosuppressed patients.
IL-21 shapes germinal center polarization via light zone B cell selection and cyclin D3 upregulation
Authors: Lina Petersone, Chun Jing Wang, Natalie M. Edner, Astrid Fabri, Spyridoula-Angeliki Nikou, Claudia Hinze, Ellen M. Ross, Elisavet Ntavli, Yassin Elfaki, Frank Heuts, Vitalijs Ovcinnikovs, Andrea Rueda Gonzalez, Luke P. Houghton, Hannah M. Li, Yang Zhang, Kai-Michael Toellner, Lucy S.K. Walker
Journal: The Journal of Experimental Medicine (2023)

Germinal center (GC) dysregulation has been widely reported in the context of autoimmunity. Here, we show that interleukin 21 (IL-21), the archetypal follicular helper T cell (Tfh) cytokine, shapes the scale and polarization of spontaneous chronic autoimmune as well as transient immunization-induced GC. We find that IL-21 receptor deficiency results in smaller GC that are profoundly skewed toward a light zone GC B cell phenotype and that IL-21 plays a key role in selection of light zone GC B cells for entry to the dark zone. Light zone skewing has been previously reported in mice lacking the cell cycle regulator cyclin D3. We demonstrate that IL-21 triggers cyclin D3 upregulation in GC B cells, thereby tuning dark zone inertial cell cycling. Lastly, we identify Foxo1 regulation as a link between IL-21 signaling and GC dark zone formation. These findings reveal new biological roles for IL-21 within GC and have implications for autoimmune settings where IL-21 is overproduced.
Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: results of a phase IIa randomized placebo-controlled trial
Authors: Stephan Weidinger, Thomas Bieber, Michael J Cork, Adam Reich, Rosamund Wilson, Sonia Quaratino, Marisa Stebegg, Nuala Brennan, Sally Gilbert, John T O’Malley, Ben Porter-Brown
Journal: British Journal of Dermatology (2023)

Abstract Background Atopic dermatitis (AD) is an inflammatory skin disease with significant unmet need. Blockade of the OX40–OX40 ligand (OX40L) costimulation pathway by targeting OX40L on antigen-presenting cells (APCs) with a fully human noncytotoxic, nondepleting anti-OX40L monoclonal antibody (amlitelimab; SAR445229; KY1005) is a novel way to modulate persistent inflammation. Objectives To assess the safety and efficacy of amlitelimab over 16 weeks in adults with AD in a phase IIa double-blind placebo-controlled study. Methods The study was conducted at 19 hospitals in Germany, Poland, Spain and the UK. Eligible patients with moderate-to-severe AD were randomized (1 : 1 : 1) to low-dose intravenous (IV) amlitelimab (200 mg), high-dose IV amlitelimab (500 mg) or placebo, followed by three maintenance doses (50% of loading dose) at 4, 8 and 12 weeks, with safety follow-up to week 36. The co-primary endpoints were the incidence of treatment-emergent adverse events (all patients who received ≥ 1 dose of the study drug) and mean percentage change in Eczema Area and Severity Index (EASI) to week 16 (full analysis set). Results Between 13 December 2018 and 12 May 2020, 89 patients were randomly assigned to low- (n = 29) or high-dose amlitelimab (n = 30) or placebo (n = 29), of whom 88 proceeded to treatment [37 women (42%), 51 (58%) men; mean (SD) age 33.6 (11.9) years]. Amlitelimab was generally well tolerated with an unremarkable safety profile; no hypersensitivity events were reported. For the primary endpoint, the least square mean percentage change in EASI from baseline to week 16 was –80.12% [95% confidence interval (CI) –95.55 to –64.68; P = 0.009 vs. placebo] and –69.97% (95% CI –85.04 to –54.60; P = 0.07 vs. placebo) for the low- (n = 27) and high-dose (n = 27) amlitelimab groups, respectively, vs. –49.37% (95% CI –66.02 to –32.72) for placebo (n = 24). Numerically greater reductions in EASI were observed for amlitelimab vs. placebo from weeks 2 to 16. Conclusions Novel targeting of OX40L-expressing APCs with amlitelimab was well tolerated and resulted in clinically meaningful improvements in AD.
Imaging Biomarkers in the Management of Light-Chain Cardiac Amyloidosis
Authors: Sarah A. M. Cuddy
Journal: JAMA Cardiology (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
Selective Extracellular Matrix Guided Mesenchymal Stem Cell Self‐Aggregate Engineering for Replication of Meniscal Zonal Tissue Gradient in a Porcine Meniscectomy Model
Authors: Sujin Noh, Yong Jun Jin, Dong Il Shin, Hyeon Jae Kwon, Hee‐Woong Yun, Kyu Min Kim, Jae‐Young Park, Jun Young Chung, Do Young Park
Journal: Advanced Healthcare Materials (2023)

Degenerative meniscus tears (DMTs) are prevalent findings in osteoarthritic knees, yet current treatment is mostly limited to arthroscopic partial meniscectomy rather than regeneration, which further exacerbates arthritic changes. Translational research regarding meniscus regeneration is hindered by the complex, composite nature of the meniscus which exhibit a gradient from inner cartilage-like tissue to outer fibrous tissue, as well as engineering hurdles often requiring growth factors and cross-linking agents. Here, a meniscus zonal tissue gradient is proposed using zone-specific decellularized meniscus extracellular matrix (DMECM) and autologous synovial mesenchymal stem cells (SMSC) via self-aggregation without the use of growth factors or cross-linking agents. Combination with zone-specific DMECM during self-aggregation of MSCs forms zone-specific meniscus tissue that reflects the respective DMECM harvest site. The implantation of these constructs leads to the regeneration of meniscus tissue resembling the native meniscus, demonstrating inner cartilaginous and outer fibrous characteristics as well as recovery of native meniscal microarchitecture in a porcine partial meniscectomy model at 6 months. In all, the findings offer a potential regenerative therapy for DMTs that may improve current partial meniscectomy-based patient care.
FOxTROT Study Results: Some Burning Questions Need Answers
Authors: Sakti Chakrabarti, Amit Mahipal
Journal: Journal of Clinical Oncology (2023)

With great interest, we read the article by Morton et al 1 that reported the long-awaited mature results of the FOxTROT study.The FOxTROT study is the first phase III study, to date, that evaluated the role of neoadjuvant chemotherapy (NAC) in patients with locally advanced colon cancer (radiologically staged T3-4, N0-2, M0) and provided several clinically important information as follows: (1) NAC effectively downstages tumors, allowing R0 resection in a significantly higher proportion of patients; (2) NAC is safe and improves disease control rate compared with the current standard of care consisting of up-front surgery, followed by riskadapted adjuvant chemotherapy; and (3) the study provides prospective data demonstrating the lack of potent antitumor activity of chemotherapy against deficient mismatch repair tumors.However, we would request the authors to share some critical data that will further clarify the role of NAC in patients with operable colon cancer, as outlined below
Contemporary concepts on periodontal complications from prosthetic and restorative therapies
Authors: Stefano Gracis, Arturo Llobell, Stephen J. Chu
Journal: Periodontology 2000 (2023)

Abstract The clinical outcome of every prosthetic and restorative procedure depends on the maintenance of a healthy periodontium. It is, therefore, important that the prosthodontist and restorative dentist cause no harm or permanent damage to the underlying hard and soft tissues when performing clinical procedures necessary to carry out the planned treatment. Several factors involved in these procedures have been described to have an impact on gingival health. For the present article, a selection of four of these factors are presented with the goal of evaluating the current trends and their influence on periodontal structures: (1) tooth preparation configuration and apical extension, (2) gingival tissue sulcular expansion/retraction, (3) prosthetic contours, and (4) prosthesis marginal adaptation and the consequences of excess cement remnants. Based on the available scientific evidence and clinical experience, recommendations for the practitioner are given.
Will Targeted Axillary Surgery Suffice for Adjuvant Treatment Decision-Making?
Authors: Margaret S. Pichardo, Jennifer Q. Zhang, Oluwadamilola M. Fayanju
Journal: JAMA Surgery (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Errors in Results and Tables
Journal: JAMA Psychiatry (2023)

Thomas Santo Jr, MPH; Brodie Clark, BPsych; Matt Hickman, PhD; Jason Grebely, PhD; Gabrielle Campbell, PhD; Luis Sordo, MD, PhD; Aileen Chen, BPsych; Lucy Thi Tran, BPsychSc; Chrianna Bharat, BSc; Prianka Padmanathan, MRCPsych; Grainne Cousins, PhD; Julie Dupouy, MD, PhD; Erin Kelty, PhD; Roberto Muga, MD, PhD; Bohdan Nosyk, PhD; Jeong Min, MSc; Raimondo Pavarin, MPH; Michael Farrell, MD; Louisa Degenhardt, PhD
Randomized Phase II Trial of Dendritic Cell/Myeloma Fusion Vaccine with Lenalidomide Maintenance after Upfront Autologous Hematopoietic Cell Transplantation for Multiple Myeloma: BMT CTN 1401
Authors: David J. Chung, Nina Shah, Juan Wu, Brent Logan, Lina Bisharat, Natalie Callander, Giulia Cheloni, Kenneth Anderson, Thinle Chodon, Binod Dhakal, Steve Devine, Poorvi Somaiya Dutt, Yvonne Efebera, Nancy Geller, Haider Ghiasuddin, Peiman Hematti, Leona Holmberg, Alan Howard, Bryon Johnson, Dimitra Karagkouni, Hillard M. Lazarus, Ehsan Malek, Philip McCarthy, David McKenna, Adam Mendizabal, Ajay Nooka, Nikhil Munshi, Lynn O'Donnell, Aaron P. Rapoport, Jane Reese, Jacalyn Rosenblatt, Robert Soiffer, Dina Stroopinsky, Lynne Uhl, Ioannis S. Vlachos, Edmund K. Waller, James W. Young, Marcelo C. Pasquini, David Avigan
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Vaccination with dendritic cell (DC)/multiple myeloma (MM) fusions has been shown to induce the expansion of circulating multiple myeloma–reactive lymphocytes and consolidation of clinical response following autologous hematopoietic cell transplant (auto-HCT). Patients and Methods: In this randomized phase II trial (NCT02728102), we assessed the effect of DC/MM fusion vaccination, GM-CSF, and lenalidomide maintenance as compared with control arms of GM-CSF and lenalidomide or lenalidomide maintenance alone on clinical response rates and induction of multiple myeloma–specific immunity at 1-year posttransplant. Results: The study enrolled 203 patients, with 140 randomized posttransplantation. Vaccine production was successful in 63 of 68 patients. At 1 year, rates of CR were 52.9% (vaccine) and 50% (control; P = 0.37, 80% CI 44.5%, 61.3%, and 41.6%, 58.4%, respectively), and rates of VGPR or better were 85.3% (vaccine) and 77.8% (control; P = 0.2). Conversion to CR at 1 year was 34.8% (vaccine) and 27.3% (control; P = 0.4). Vaccination induced a statistically significant expansion of multiple myeloma–reactive T cells at 1 year compared with before vaccination (P = 0.024) and in contrast to the nonvaccine arm (P = 0.026). Single-cell transcriptomics revealed clonotypic expansion of activated CD8 cells and shared dominant clonotypes between patients at 1-year posttransplant. Conclusions: DC/MM fusion vaccination with lenalidomide did not result in a statistically significant increase in CR rates at 1 year posttransplant but was associated with a significant increase in circulating multiple myeloma–reactive lymphocytes indicative of tumor-specific immunity. Site-specific production of a personalized cell therapy with centralized product characterization was effectively accomplished in the context of a multicenter cooperative group study. See related commentary by Qazilbash and Kwak, p. 4703
Self-Help Habit Replacement in Individuals With Body-Focused Repetitive Behaviors
Authors: Steffen Moritz, Danielle Penney, Franziska Missmann, Sarah Weidinger, Stella Schmotz
Journal: JAMA Dermatology (2023)

Body-focused repetitive behaviors (BFRBs; eg, skin picking) encompass a set of conditions at the interface of dermatology and psychiatry/psychology. The disorder is prevalent but currently underdiagnosed and undertreated.